Opioid abuse and dependence are growing public health problems in the United States. While rates of heroin use have remained fairly stable over the past several years, abuse and dependence on prescription opioids have shown sharp increases over the past decade. In 2006 (SAMHSA, 2007b), it was estimated that approximately one million people were prescription opioid-dependent (based upon DSM-IV criteria) adding to the current one million people estimated by the Office of National Drug Control Policy to be addicted to heroin. While there are existing pharmacotherapies approved for the treatment of opioid dependence in the United States, the most efficacious (buprenorphine and methadone) are restricted in use to specified practice conditions, thus limiting their availability to patients. Substance P, a neurokinin peptide, is widely distributed throughout human brain and its receptors are highly expressed in brain regions involved in affect and reward. Recent evidence suggests that inactivation of substance P receptors (NK1), either through genetic deletion or pharmacological blockade, significantly attenuates the rewarding effects of opioids in an array of non-human laboratory models. We hypothesize that pretreatment with a substance P receptor antagonist may reduce the direct pharmacodynamic actions of mu opioid agonists related to their abuse liability and rewarding effects in humans. Aprepitant is a NK1 receptor antagonist used clinically for its anti-emetic action. The proposed studies will enroll healthy adult male and female volunteers with histories of illicit opioid use. Two inpatient experiments will be conducted that incorporate double-blind, placebo-controlled, randomized, within-subject designs, and include careful evaluation of full dose-effect and time action curves on multi-dimensional outcomes. Experiment 1 will examine the effects of acute doses of aprepitant alone and in combination with acute doses of oral oxycodone and intranasal oxycodone in non-dependent opioid abusers (n=10). Pharmacodynamic outcomes will include subject- and observer-rated measures related to abuse potential, psychomotor performance and physiological indices. Experiment 2 will examine the effects of chronic dosing with aprepitant and test its ability at steady state to alter the reinforcing effects of intranasal oxycodone (n=10). A progressive ratio self-administration procedure will be employed in this study to examine directly opioid reinforcement. Additionally, the pharmacodynamic interactions after repeated dosing of aprepitant with oxycodone on an array of measures will be examined during the sample sessions. Thus, these studies will provide new information on the safety of NK1 antagonist treatment under both acute and chronic dosing conditions and on its potential efficacy to alter the abuse liability and reinforcing properties of oxycodone. These studies are responsive to the RFA (DA-06-002) as they will provide proof-of-concept data and assess the utility of a novel CNS target, the substance P receptor, by evaluating the potential efficacy of an NK1 receptor antagonist, aprepitant, to reduce the abuse liability and reinforcing effects of opioids in humans. PUBLIC HEALTH RELEVANCE: This project will test the hypothesis that blockade of substance P receptors in human brain may reduce the effects of opioids related to their abuse. The substance P system has not been examined as a potential target for the development of treatments for opioid abuse and dependence. Thus, these studies, conducted in healthy humans, will provide fundamental information regarding the potential for this system as a target for development of new treatment agents for opioid use disorders.